Use of basic alkali metal salts for manufacturing transdermal therapeutic system

ABSTRACT

A process for manufacturing transdermal systems comprising free active substance bases is characterized in that the free active substance base is liberated, during the manufacture of the system, from active substance salts by conversion with a basic alkaline metal salt.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Many medicinal active agents contain one or more basic nitrogen atoms intheir molecule and can therefore be utilized in pharmaceuticalpreparations either as a free base or as a salt of the active substancebase with an acid which is suitable for this purpose. Salts have theadvantage of better water solubility, which is important for oraladministration, and in many cases also the advantage of betterstability. A further advantage is that active substance salts are oftenmore easily crystallised, or it is anyway only the active substance saltwhich is crystalline at room temperature. This is the reason why manyactive substances are manufactured and available only in the form oftheir salts.

2. Description of the Preferred Embodiment

For transdermal administration, however, the active substance salts areunsuitable since due to their higher polarity they are not capable ofpenetrating the lipophile barrier of the stratum corneum in thequantities required for the therapeutic purpose.

Thus, it is necessary to transform active substance salts into theirfree base in order to utilize them in transdermal systems.

Basically, there are two types of transdermal therapeutic systems (TTSs)which dominate the market, namely the so-called matrix systems and thereservoir systems.

A matrix system consists in the simplest case of a backing layer, aself-adhesive active agent-containing matrix, and a protective film orsheet which is to be removed prior to use. In more complicated designs,the matrix has a multi-layer structure, while there is no necessity foreach of the layers to be self-adhesive. Incorporation of membranes intothe matrix for control of active substance delivery may also beprovided.

A matrix system may also consist of a non-self-adhesive activesubstance-containing matrix which, for fixation on the skin, is providedwith an active substance-free super-imposed patch which projects beyondsaid matrix on all sides.

Reservoir systems consist of a bag made of an activesubstance-impermeable film or sheet, and a membrane which is permeableat least to the active substance. The bag is filled with a liquid orgel-like active substance preparation. For anchoring the system on theskin, the membrane is in most cases equipped with an adhesive. Thesesystems, too, are provided with a protective sheet to be removed priorto use.

Technically, it is of course no problem to convert an active substancesalt into the free base. The most simple way to achieve this is todissolve the active substance salt in water and to add an auxiliary basesuch as NaOH. The resultant active substance base either precipitates onaccount of its lesser water-solubility and can be filtered off, or itmust be extracted with a suitable organic solvent, such as methylenechloride. A disadvantage of this procedure is that the free base must bespecially processed so as to be usable for the manufacture of thetransdermal systems.

An ideal process enables the release of the free base during themanufacture of the system in situ without the manufacturing processthereby becoming considerably more complicated than in the case ofdirect use of the free base.

Such a process is described in EP 0 272 562. In this process, adhesivesare used which themselves possess basic groups and are therebythemselves, as auxiliary bases, capable of liberating the free base. Thedisadvantage of this process is that the number of these functionalbasic groups in the adhesive is limited, and that for this reason onlysmall amounts of active substance salts can be converted into their freebases.

SUMMARY OF THE INVENTION

It is the object of the present invention to develop a process whichenables the conversion also of larger amounts of active substance andaccordingly avoids the disadvantages of the prior art.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Surprisingly, it was found that it is possible to convert activesubstance salts in organic solvents, such as methanol, ethanol,ispropanol, methyl ethyl ketone, into their free bases by conversionwith basic alkaline metal salts, especially alkaline silicates, such astrisilicates and metasilicates of sodium or potassium. Trisilicates andmetasilicates are available in various degrees of hydration, which are,however, to be regarded as equivalent in terms of their suitability.

These silicates are salts of a weak acid with a strong base, andtherefore react as a base. This means that in the presence of activesubstance salts which are to be considered weak acids they are convertedto the free silicic acids. The free silicic acids are unstable and reactfurther to polymeric silicon dioxide under elimination of water. Thismakes the reaction irreversible, and the complete conversion of theactive substance salts into their free bases is possible despite the lowbasicity of the silicates. A precondition thereof is of course that thesilicate is used at least in the stoichiometrically required amount. Thefact that the reaction is irreversible renders the silicates superior toother auxiliary bases such as ethanolamines, since the latter compoundspossess a basicity comparable to that of the active substance bases,with the result that only equilibriums occur wherein an almostquantitative conversion of the active substance salt into the free baseis possible only under use of an excess of auxiliary base. In addition,these auxiliary bases are themselves capable of entering the skin orpermeating therethrough and of causing local skin irritations or toxicside effects.

It is surprising and unexpected that alkaline metal silicates,especially trisilicates and metasilicates of sodium and potassium, canbe utilized for this purpose in organic solvents since both the activesubstance salts and the silicates have only very low solubility in thesesolvents.

The best solubility for these silicates was found in methanol andethanol and was determined to be only 0.01% (g/g). Nevertheless, it ispossible to use solvents with even less solubility for silicates, suchas isopropanol, acetone, methyl ethyl ketone, ethyl acetate and mixturesof the aforementioned solvents.

It is furthermore surprising that despite this low solubility one issuccessful in achieving, within acceptable periods of time, a completeconversion of the active substance salts into their free bases.Normally, the complete conversion at room temperature takes only about2-3 days; it can be shortened to about 24 hours by increasing thetemperature to about 35-40° C. Attempts to use silicates of calcium ormagnesium failed since, owing to the multivalent cations, they arepractically insoluble in organic solvents. Basic aluminium-containingmixed silicates have proved just as unsuitable.

it is possible to check microscopically if the conversion has beencompleted. If the conversion is complete, none of the active substancesalt crystals, which are poorly soluble in organic solvents, are visibleany more.

For the manufacture of matrix systems it is important that the solventsused for the conversion are highly compatible with the adhesivesdissolved in organic solvents. This is the case with the above-mentionedsolvents, however, the selection mentioned is only exemplary.

Reaction products of the alkaline silicates are silicon dioxide and thesodium or potassium salt of the acid contained in the active substance.Silicon dioxide is a compound which is to be considered totally atoxic.For this reason, from the toxicological standpoint, it is not necessaryto remove silicon dioxide from the active substance solution. Shouldthis be required from a technical point of view, one only needs toinclude a filtration step.

Also, the basic silicates themselves are to be regarded as practicallyatoxic. They are utilized without problems in many industrial orhousehold detergents to set the detergent to a basic pH. The onlyreaction which might possibly have to be expected is skin irritation dueto their basicity. Since, however, their solubility in the polymers orreservoir formulations used for matrix systems is low, this too isnormally not to be expected. Only in the case of very highconcentrations, which in matrix systems lead to the undissolved silicatecrystals coming into contact with the skin, there is a risk of localskin irritations. However, by filtering-off one can very easily removeany excess silicates in the converted active substance solution. Thefiltration step is also advisable if the active substance tends to showinstabilities in the presence of basic substances. After filtration, thepH in the TTS matrix, or in the reservoir of the reservoir systems, isdetermined only by the basicity of the active substance itself—if noother pH regulators are added.

The use of basic alkaline metal salts, in particular, of alkaline metalsilicates, and especially of metasilicates and trisilicates of sodium orpotassium, for in-situ conversion of salts of basic active substancesinto the free active substance bases during the manufacture oftransdermal therapeutic systems, represents a considerable improvementover the prior art. The conversion takes place under very mildconditions, and it is not necessary to isolate the active substance baseor to separate the reaction products of the auxiliary base. Possibleunreacted excess amounts of the silicates need not be separated either,since as a consequence of their being incorporated in the transdermalsystem there is no risk of any side effects whatsoever.

EXAMPLES Example 1

20 g of(−)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)-ethyl]amino]-1-naphtholhydrochloride are stirred, together with 8.0 g of sodium metasilicate or9.1 g of sodium trisilicate, in 35 ml of ethanol for 48 hours at roomtemperature. Optionally, the active substance solution is now filtrated,and 6.0 g of polyvinyl pyrrolidone (Kollidon F90, from Bayer), in theform of a 25% (g/g) solution in ethanol, and 250 g of a 70% solution ofan amino-resistant silicone adhesive (Q7-4301, from Dow Corning) inheptane are added, and the mass is subsequently homogenised bymechanical stirring.

Subsequently, in order to prepare the patch matrix the mass is coated onan appropriate, abhesively equipped film, and the solvents are removedby drying for 20 minutes at 50° C. The coating weight of the driedmatrix film is 50 g/m².

The dried matrix film is laminated with a 23-μm-thick polyester film.The individual plasters are punched out of the complete laminate.

Example 2

25 g of(−)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl]ethyl]amino]-1-naphtholhydrochloride are stirred, together with 14.7 g of sodium metasilicateor 16.8 g of sodium trisilicate, in 40 ml of ethanol for 48 hours atroom temperature. Optionally, the active substance solution is nowfiltrated, and 9.2 g of oleyl alcohol, 63.2 g of a 52% solution of apolyacrylate adhesive (Durotak 387-2287, from National Starch &Chemical), and 22.8 g of a 4004 (g/g) solution of Eudragit E 100(Röhm-Pharma) are added, and the mass is subsequently homogenised bymechanical stirring.

Subsequently, for preparation of the patch matrix, the mass is coated onan appropriate, abhesively equipped film, and the solvents are removedby drying for 20 minutes at 50° C. The coating weight of the driedmatrix film is 80 g/m².

The dried matrix film is laminated with a 23-μm-thick polyester film.The individual plasters are punched out of the complete laminate.

Example 3

50 g of scopolamine hydrobromide are stirred, together with 13.8 g ofsodium metasilicate or 15.7 g of sodium trisilicate, in 40 ml of ethanolfor 48 hours at room temperature. Optionally, the active substancesolution is now filtrated, and 32 g of oleic acid and 480 g of a 52%solution of a polyacrylate adhesive (Durotak 387-2253, of NationalStarch & Chemical) are added, and the mass is subsequently homogenisedby mechanical stirring.

Subsequently, for preparation of the patch matrix, the mass is coated onan appropriate, abhesively equipped film, and the solvents are removedby drying for 20 minutes at 50° C. The coating weight of the driedmatrix film is 90 g/m².

The dried matrix film is laminated with a 23-μm-thick polyester film.The individual plasters are punched out of the complete laminate.

The invention has been described with particular emphasis on thepreferred embodiments, but variations and modifications within thespirit and scope of the invention may occur to those skilled in the artto which the invention pertains.

What is claimed is:
 1. A process for manufacturing transdermal systemscomprising free active substance bases, said process comprising thesteps of manufacturing the systems and liberating the free activesubstance base by converting active substance salts with a basicalkaline metal salt, wherein said basic alkaline metal salt is asilicate, and wherein the active substance salts are converted in anorganic solvent.
 2. The process for manufacturing transdermal systemscomprising free active substance bases according to claim 1, wherein thesilicate is selected from the group consisting of a sodium and potassiumsilicate.
 3. The process for manufacturing transdermal systemscomprising free active substance bases according to claim 1 wherein thesilicate is selected from the group consisting of a trisilicate andmetasilicate.
 4. The process for manufacturing transdermal systemscomprising free active substance bases according to claim 1, wherein theorganic solvent is selected from the group consisting of ethanol,methanol, methyl ethyl ketone, isopropanol, ethylene glycol, propyleneglycol and mixtures thereof.
 5. The process for manufacturingtransdermal systems according to claim 1, comprising the additionalsteps of suspending the active substance salt along with the basicalkaline metal salt in the organic solvent to form a solution orsuspension, stirring the solution until quantitative conversion of theactive substance salt is achieved, and[, subsequently] adding thequantitative converted active substance salt to a polymer mass which isdissolved in an organic solvent.
 6. The process for manufacturingtransdermal systems cording to claim 5, wherein the dissolved polymermass is an adhesive.
 7. The process for manufacturing transdermalsystems according to claim 5 comprising the additional step of filteringthe solution or suspension of the basic alkaline metal salt and theactive substance salt following the conversion and prior tobing added tothe polymer mass.
 8. The process for manufacturing transdermal systemsaccording to claim 6 wherein for manufacture of a matrix system,comprising the additional steps of coating the polymer mass on asuitable, adhesively equipped film or sheet, drying the film or sheet toremove the solvents, laminating the dried film with a suitable film orsheet, and punching out the transdermal systems from the resultantlaminate.
 9. The process for manufacturing transdermal systems accordingto claim 6 for manufacture of a reservoir system, and further comprisingthe steps of completely converting the active substance salt, andfilling a bag comprising an impermeable backing layer and a membranepermeable at least to the active substance with the solvent.
 10. Theprocess for manufacturing transdermal systems according to claim 9, andfurther comprising the steps of providing the membrane of the bag withan adhesive layer for adhesion to the skin.
 11. The process formanufacturing transdermal systems according to claim 1, wherein theactive substance is selected from the group consisting ofantihypersensitives, antiemetics, antiparkinsonian agents,antidepressants, antiasthmatics, analgesics and antiallergic agents. 12.The process for manufacturing transdermal systems according to claim 1,wherein that the active substance is a D2-agonist and especially(−)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol.